Ocular formulations for drug-delivery and protection of the anterior segment of the eye

Abstract

The present application relates to topical formulations comprising Compound-Ior its free base, and a second active agent selected from nicotinic acid, nicotinamide, and vitamin K, and a combination thereof, for treating ocular neovascularization. The present application also relates to pharmaceutical compositions comprising particles of Compound-I or its free base, and suspension formulations comprising the particle compositions of Compound-I or its free base.

1 . A topical, ocular, suspension formulation, comprising:
 a. particles of a first active agent of Formula II:   
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof; and 
         b. one or more pharmaceutically acceptable excipients selected from hydroxy propyl methyl cellulose (HPMC), carboxylmethyl cellulose and salts thereof, and hydroxyl ethyl cellulose (HEC); 
       
       wherein the first active agent or the pharmaceutically acceptable salt thereof is present in about 0.1% to about 2.0% (w/v), and the particles have a mean diameter of between 100 nm and 100 μm. 
     
     
         2 . The formulation of  claim 1 , wherein the first active agent is Compound-I: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The formulation of  claim 1 , further comprising a second active agent, or a pharmaceutically acceptable salt thereof, wherein the second active agent is nicotinic acid, nicotinamide, or vitamin K, or a combination thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the particles have a mean diameter of between 30 μm and 60 μm. 
     
     
         5 . The formulation of  claim 1 , wherein the particles have a mean diameter of between 1 μm and 5 μm. 
     
     
         6 . The formulation of  claim 1 , wherein the particles have a mean diameter of about 3 μm, about 30 μm, about 35 μm, or about 50 μm. 
     
     
         7 . The formulation of  claim 1 , comprising about 0.1% to about 1.0% (w/v) of the compound of Formula II or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The formulation of  claim 1 , comprising about 0.2% to about 1.0% (w/v) of the compound of Formula II or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The formulation of  claim 1 , comprising about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1.0% (w/v) of the compound of Formula II or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The formulation of  claim 3 , wherein the second active agent is present in an amount of less than 10 μM. 
     
     
         11 . The formulation of  claim 3 , wherein the second active agent is present in an amount of about 1 μM, about 2 μM, about 3 μM, about 4 μM, or about 5 μM. 
     
     
         12 . The formulation of  claim 3 , wherein the second active agent is present in an amount of about 1 μM. 
     
     
         13 . The formulation of  claim 1 , further comprising one or more excipients selected from a non-ionic liquid polymer and a hydrophilic non-ionic surfactant. 
     
     
         14 . The formulation of  claim 13 , wherein the non-ionic liquid polymer is of the alkyl aryl polyether alcohol type. 
     
     
         15 . The formulation of  claim 13 , wherein the hydrophilic non-ionic surfactant is poloxamer. 
     
     
         16 . The formulation of  claim 1 , further comprising one or more excipients are selected from Polysorbate (Tween) 80, Poloxamer (Pluronic) F-127, Poloxamer 407, Povidone (PVP K-29/32 or K-30), and Tyloxapol, and a combination thereof. 
     
     
         17 . The formulation of  claim 1 , further comprising a stabilizer for the second active agent. 
     
     
         18 . The formulation of  claim 1 , wherein the formulation has a pH of about 6. 
     
     
         19 . The formulation of  claim 1 , wherein the one or more pharmaceutically acceptable excipients are selected from one or more of hydroxyl propyl methyl cellulose (HPMC) and carboxylmethyl cellulose and salts thereof. 
     
     
         20 . The formulation of  claim 1 , wherein the one or more pharmaceutically acceptable excipients are selected from one or more of hydroxyl propyl methyl cellulose (HPMC) and hydroxyl ethyl cellulose (HEC).